In the previous period of funding we developed gene transfer vectors based on the herpes simplex virus[unreadable] (HSV) to deliver genes with high efficiency to peripheral sensory neurons. We have exploited this property[unreadable] to develop non-replicating HSV vectors that provide an analgesic effect in models of somatic pain[unreadable] (inflammatory pain, neuropathic pain, and pain resulting from cancer) and visceral pain (bladder[unreadable] inflammation). In this renewal we focus our efforts to further develop HSV vectors for treatment of acute and[unreadable] chronic pain related to diabetes and painful bladder syndromes. Project 1 will explore the use of HSV-mediated[unreadable] transfer of genes that produce inhibitory neurotransmitters (glutamic acid decaraboxylase and[unreadable] proenkephalin) and anti-inflammatory peptides (IL4 and TNFDSR) in models of painful diabetic neuropathy.[unreadable] Project 2 will explore the analgesic effect of these vectors in acute and chronic rodent models of bladder[unreadable] pain. Project 3 will use a vector-based functional genomics approach to identify and characterize novel[unreadable] cellular gene products that inhibit or negatively modulate the activity of the vanilloid receptor TRPV1.[unreadable] Projects 1 and 2 are designed to provide preclinical evidence for vectors that may be developed for novel[unreadable] treatments of human disease, while Project 3 will lead to the identification and evaluation of novel gene[unreadable] products that would then be tested in a similar fashion. Administration (Core A), Preclinical Vector Production[unreadable] (Core B) and Gene Transfer Assays and Imaging (Core C) cores directly support the activities of all three[unreadable] projects. We believe this to be a timely and highly innovative proposal which is likely to provide new[unreadable] approaches to treatment of chronic pain related to diabetes and inflammation.